Association of the time of day of EVT with clinical outcomes and benefit from successful recanalization after stroke

Experimental and neuroimaging studies suggest an influence of the time of day on acute infarct growth, but whether this could inform patient selection for acute treatments is uncertain. In a multicenter cohort of 9357 stroke patients undergoing endovascular treatment, morning treatment (05:00–10:59) was associated with lowest 90-day mRS scores (adjusted odds ratio, 1.27 [95% CI, 1.08–1.47]; p = 0.004). The association between successful recanalization and outcome was stronger in morning compared to evening-treated patients (pia = 0.046) with treatment benefit persisting until 24 h for morning-treated compared to 11.5 h for evening-treated patients suggesting that the time of day might inform patient selection for EVT

Microstructural white matter integrity in relation to vascular reactivity in Dutch-type hereditary cerebral amyloid angiopathy

Cerebral Amyloid Angiopathy (CAA) is characterized by cerebrovascular amyloid-β accumulation leading to hallmark cortical MRI markers, such as vascular reactivity, but white matter is also affected. By studying the relationship in different disease stages of Dutch-type CAA (D-CAA), we tested the relation between vascular reactivity and microstructural white matter integrity loss. In a cross-sectional study in D-CAA, 3 T MRI was performed with Blood-Oxygen-Level-Dependent (BOLD) fMRI upon visual activation to assess vascular reactivity and diffusion tensor imaging to assess microstructural white matter integrity through Peak Width of Skeletonized Mean Diffusivity (PSMD). We assessed the relationship between BOLD parameters - amplitude, time-to-peak (TTP), and time-to-baseline (TTB) - and PSMD, with linear and quadratic regression modeling. In total, 25 participants were included (15/10 pre-symptomatic/symptomatic; mean age 36/59 y). A lowered BOLD amplitude (unstandardized β = 0.64, 95%CI [0.10, 1.18], p = 0.02, Adjusted R2 = 0.48), was quadratically associated with increased PSMD levels. A delayed BOLD response, with prolonged TTP (β = 8.34 × 10-6, 95%CI [1.84 × 10-6, 1.48 × 10-5], p = 0.02, Adj. R2 = 0.25) and TTB (β = 6.57 × 10-6, 95%CI [1.92 × 10-6, 1.12 × 10-5], p = 0.008, Adj. R2 = 0.29), was linearly associated with increased PSMD. In D-CAA subjects, predominantly in the symptomatic stage, impaired cerebrovascular reactivity is related to microstructural white matter integrity loss. Future longitudinal studies are needed to investigate whether this relation is causal.</p

Microstructural white matter integrity in relation to vascular reactivity in Dutch-type hereditary cerebral amyloid angiopathy

Cerebral Amyloid Angiopathy (CAA) is characterized by cerebrovascular amyloid-β accumulation leading to hallmark cortical MRI markers, such as vascular reactivity, but white matter is also affected. By studying the relationship in different disease stages of Dutch-type CAA (D-CAA), we tested the relation between vascular reactivity and microstructural white matter integrity loss. In a cross-sectional study in D-CAA, 3 T MRI was performed with Blood-Oxygen-Level-Dependent (BOLD) fMRI upon visual activation to assess vascular reactivity and diffusion tensor imaging to assess microstructural white matter integrity through Peak Width of Skeletonized Mean Diffusivity (PSMD). We assessed the relationship between BOLD parameters – amplitude, time-to-peak (TTP), and time-to-baseline (TTB) – and PSMD, with linear and quadratic regression modeling. In total, 25 participants were included (15/10 pre-symptomatic/symptomatic; mean age 36/59 y). A lowered BOLD amplitude (unstandardized β = 0.64, 95%CI [0.10, 1.18], p = 0.02, Adjusted R2 = 0.48), was quadratically associated with increased PSMD levels. A delayed BOLD response, with prolonged TTP (β = 8.34 × 10−6, 95%CI [1.84 × 10−6, 1.48 × 10−5], p = 0.02, Adj. R2 = 0.25) and TTB (β = 6.57 × 10−6, 95%CI [1.92 × 10−6, 1.12 × 10−5], p = 0.008, Adj. R2 = 0.29), was linearly associated with increased PSMD. In D-CAA subjects, predominantly in the symptomatic stage, impaired cerebrovascular reactivity is related to microstructural white matter integrity loss. Future longitudinal studies are needed to investigate whether this relation is causal

Cerebral white matter injury in small vessel and Alzheimer’s disease

Alzheimer’s disease and small vessel disease are the most common causes of ageing-related cognitive impairment and dementia. In order to better understand these diseases, there is a need for sensitive brain injury markers. Measures of white matter integrity derived from diffusion MRI have been suggested as an injury marker in both conditions. The overarching aim of this thesis was to study the microstructural integrity of the white matter in Alzheimer’s disease and small vessel diseases to better understand brain injury and cognitive decline in these conditions. Four key findings emerged from my thesis: 1) small vessel diseases more than Alzheimer’s disease determine white matter diffusion MRI alterations in memory clinic patients. 2) small vessel diseases and Alzheimer’s disease could not be disentangled based on their white matter diffusion signature with the techniques we used. 3) For neither disease, critical network connections were not found to be extra vulnerable compared to non-critical connections. The effects of both small vessel diseases and Alzheimer’s disease on the white matter network seem quite diffuse. 4) Diffusion-based measures of white matter integrity appear to be a strong determinant of cognition in small vessel diseases and white matter integrity mediates the relationship between small vessel diseases burden and cognition. The work in this thesis shows that for small vessel diseases, diffusion measures are strong markers, capable of capturing relevant information about the disease. For Alzheimer’s disease, there are currently alternative markers that provide more information on relevant aspects of the disease processes and injury and are more specific to Alzheimer’s disease than diffusion measures of the white matter

Impact of thresholding on the consistency and sensitivity of diffusion MRI‐based brain networks in patients with cerebral small vessel disease

Abstract Introduction Thresholding of low‐weight connections of diffusion MRI‐based brain networks has been proposed to remove false‐positive connections. It has been previously established that this yields more reproducible scan–rescan network architecture in healthy subjects. In patients with brain disease, network measures are applied to assess inter‐individual variation and changes over time. Our aim was to investigate whether thresholding also achieves improved consistency in network architecture in patients, while maintaining sensitivity to disease effects for these applications. Methods We applied fixed‐density and absolute thresholding on brain networks in patients with cerebral small vessel disease (SVD, n = 86; ≈24 months follow‐up), as a clinically relevant exemplar condition. In parallel, we applied the same methods in healthy young subjects (n = 44; scan–rescan interval ≈4 months) as a frame of reference. Consistency of network architecture was assessed with dice similarity of edges and intraclass correlation coefficient (ICC) of edge‐weights and hub‐scores. Sensitivity to disease effects in patients was assessed by evaluating interindividual variation, changes over time, and differences between those with high and low white matter hyperintensity burden, using correlation analyses and mixed ANOVA. Results Compared to unthresholded networks, both thresholding methods generated more consistent architecture over time in patients (unthresholded: dice = .70; ICC: .70–.78; thresholded: dice = .77; ICC: .73–.83). However, absolute thresholding created fragmented nodes. Similar observations were made in the reference group. Regarding sensitivity to disease effects in patients, fixed‐density thresholds that were optimal in terms of consistency (densities: .10–.30) preserved interindividual variation in global efficiency and node strength as well as the sensitivity to detect effects of time and group. Absolute thresholding produced larger fluctuations of interindividual variation. Conclusions Our results indicate that thresholding of low‐weight connections, particularly when using fixed‐density thresholding, results in more consistent network architecture in patients with longer rescan intervals, while preserving sensitivity to disease effects

The cumulative effect of small vessel disease lesions is reflected in structural brain networks of memory clinic patients

Background and purpose: Mechanisms underlying cognitive impairment in patients with small vessel disease (SVD) are still unknown. We hypothesized that cognition is affected by the cumulative effect of multiple SVD-related lesions on brain connectivity. We therefore assessed the relationship between the total SVD burden on MRI, global brain network efficiency, and cognition in memory clinic patients with vascular brain injury. Methods: 173 patients from the memory clinic of the University Medical Center Utrecht underwent a 3 T brain MRI scan (including diffusion MRI sequences) and neuropsychological testing. MRI markers for SVD were rated and compiled in a previously developed total SVD score. Structural brain networks were reconstructed using fiber tractography followed by graph theoretical analysis. The relationship between total SVD burden score, global network efficiency and cognition was assessed using multiple linear regression analyses. Results: Each point increase on the SVD burden score was associated with 0.260 [-0.404 - -0.117] SD units decrease of global brain network efficiency ( p < .001). Global network efficiency was associated with information processing speed (standardized B = -0.210, p = .004) and attention and executive functioning (B = 0.164, p = .042), and mediated the relationship between SVD burden and information processing speed ( p = .027) but not with executive functioning ( p = .12). Conclusion: Global network efficiency is sensitive to the cumulative effect of multiple manifestations of SVD on brain connectivity. Global network efficiency may therefore serve as a useful marker for functionally relevant SVD-related brain injury in clinical trials

Does Loss of Integrity of the Cingulum Bundle Link Amyloid-β Accumulation and Neurodegeneration in Alzheimer's Disease?

Background: Alzheimer's disease is characterized by the accumulation of amyloid-β (Aβ) into plaques, aggregation of tau into neurofibrillary tangles, and neurodegenerative processes including atrophy. However, there is a poorly understood spatial discordance between initial Aβ deposition and local neurodegeneration. Objective: Here, we test the hypothesis that the cingulum bundle links Aβ deposition in the cingulate cortex to medial temporal lobe (MTL) atrophy. Methods: 21 participants with mild cognitive impairment (MCI) from the UMC Utrecht memory clinic (UMCU, discovery sample) and 37 participants with MCI from Alzheimer's Disease Neuroimaging Initiative (ADNI, replication sample) with available Aβ-PET scan, T1-weighted and diffusion-weighted MRI were included. Aβ load of the cingulate cortex was measured by the standardized uptake value ratio (SUVR), white matter integrity of the cingulum bundle was assessed by mean diffusivity and atrophy of the MTL by normalized MTL volume. Relationships were tested with linear mixed models, to accommodate multiple measures for each participant. Results: We found at most a weak association between cingulate Aβ and MTL volume (added R2 <0.06), primarily for the posterior hippocampus. In neither sample, white matter integrity of the cingulum bundle was associated with cingulate Aβ or MTL volume (added R2 <0.01). Various sensitivity analyses (Aβ-positive individuals only, posterior cingulate SUVR, MTL sub region volume) provided similar results. Conclusion: These findings, consistent in two independent cohorts, do not support our hypothesis that loss of white matter integrity of the cingulum is a connecting factor between cingulate gyrus Aβ deposition and MTL atrophy

Small vessel disease more than Alzheimer's disease determines diffusion MRI alterations in memory clinic patients

Introduction: Microstructural alterations as assessed by diffusion tensor imaging (DTI) are key findings in both Alzheimer's disease (AD) and small vessel disease (SVD). We determined the contribution of each of these conditions to diffusion alterations. Methods: We studied six samples (N = 365 participants) covering the spectrum of AD and SVD, including genetically defined samples. We calculated diffusion measures from DTI and free water imaging. Simple linear, multivariable random forest, and voxel-based regressions were used to evaluate associations between AD biomarkers (amyloid beta, tau), SVD imaging markers, and diffusion measures. Results: SVD markers were strongly associated with diffusion measures and showed a higher contribution than AD biomarkers in multivariable analysis across all memory clinic samples. Voxel-wise analyses between tau and diffusion measures were not significant. Discussion: In memory clinic patients, the effect of SVD on diffusion alterations largely exceeds the effect of AD, supporting the value of diffusion measures as markers of SVD.Fil: Finsterwalder, Sofia. Ludwig Maximilians Universitat; AlemaniaFil: Vlegels, Naomi. University of Utrecht; Países BajosFil: Gesierich, Benno. Ludwig Maximilians Universitat; AlemaniaFil: Araque Caballero, Miguel Á.. Ludwig Maximilians Universitat; Alemania. German Center for Neurodegenerative Diseases; AlemaniaFil: Weaver, Nick A.. University of Utrecht; Países BajosFil: Franzmeier, Nicolai. Ludwig Maximilians Universitat; AlemaniaFil: Georgakis, Marios K.. Ludwig Maximilians Universitat; AlemaniaFil: Konieczny, Marek J.. Ludwig Maximilians Universitat; AlemaniaFil: Koek, Huiberdina L.. University of Utrecht; Países BajosFil: Karch, Celeste M.. Washington University in St. Louis; Estados UnidosFil: Graff Radford, Neill R.. Mayo Clinic In Jacksonville; Estados UnidosFil: Salloway, Stephen. Butler Hospital; Estados UnidosFil: Oh, Hwamee. University Brown; Estados UnidosFil: Allegri, Ricardo Francisco. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; ArgentinaFil: Chhatwal, Jasmeer P.. Harvard Medical School; Estados UnidosFil: Jessen, Frank. Universitat zu Köln; Alemania. German Center for Neurodegenerative Diseases; AlemaniaFil: Düzel, Emrah. Otto-von-Guericke-Universität Magdeburg; Alemania. German Center for Neurodegenerative Diseases; AlemaniaFil: Dobisch, Laura. Otto-von-Guericke-Universität Magdeburg; Alemania. German Center for Neurodegenerative Diseases; AlemaniaFil: Metzger, Coraline. Otto-von-Guericke-Universität Magdeburg; Alemania. German Center for Neurodegenerative Diseases; AlemaniaFil: Peters, Oliver. German Center for Neurodegenerative Diseases; Alemania. Freie Universität Berlin; AlemaniaFil: Incesoy, Enise I.. Freie Universität Berlin; AlemaniaFil: Priller, Josef. Freie Universität Berlin; Alemania. German Center for Neurodegenerative Diseases; AlemaniaFil: Spruth, Eike J.. Freie Universität Berlin; Alemania. German Center for Neurodegenerative Diseases; AlemaniaFil: Schneider, Anja. German Center for Neurodegenerative Diseases; Alemania. University Hospital Bonn; AlemaniaFil: Fließbach, Klaus. German Center for Neurodegenerative Diseases; Alemania. University Hospital Bonn; AlemaniaFil: Buerger, Katharina. Ludwig Maximilians Universitat; Alemania. German Center for Neurodegenerative Diseases; AlemaniaFil: Janowitz, Daniel. Ludwig Maximilians Universitat; AlemaniaFil: Teipel, Stefan J.. German Center for Neurodegenerative Diseases; Alemania. Rostock University Medical Center; AlemaniaFil: Kilimann, Ingo. German Center for Neurodegenerative Diseases; Alemania. Rostock University Medical Center; AlemaniaFil: Laske, Christoph. German Center for Neurodegenerative Diseases; Alemania. University of Tübingen; Alemani